Summary: Ligands and receptors in the Tumor Necrosis Factor (TNF) superfamily exert important modifying effects on innate and adaptive immune responses. The 'death receptor' subfamily of TNF receptors is known to mediated programmed cell death through recruitment of caspases to the intracellular tail of the receptor. In the immune system, signaling through death receptors eliminates autoreactive T and B cells at a number of critical checkpoints in peripheral differentiation. Elimination of the death receptor Fas/CD95 results in autoimmunity through blocking elimination of autoreactive T and B cells. However, recent experimental evidence suggests that the adapter protein FADD and the initiator caspase-8 enzyme can also mediate some aspects of T cell activation. To study the cell-type specific function of death receptor signaling, we have generated transgenic mice overexpressing v-FLIP, a potent viral blocker of death receptor signal transduction. We have also been studying the function of the TNF receptor DR3, a lymphocyte specific death-domain containing receptor, in T cell homeostasis and differentiation. The long-term goals of these studies are to better understand the cross-talk between apoptosis and survival signaling pathways in various lymphocyte subsets, and study the effects of blocking specific TNFR signals on autoimmune disease models.